3 Lecture Outline Homeostasis Divisions of the ANS Cellular Organization of the ANS Pathways of the...

3

Lecture Outline

• Homeostasis

• Divisions of the ANS

• Cellular Organization of the ANS

• Pathways of the ANS

• Pharmacology of Autonomic Function

• Clinical Correlations

Autonomic Nervous System (ANS)• Involuntary or visceral nervous system• Regulates the activity of:

– Cardiac Muscle (Heart)– Smooth Muscle ( In Hollow Organs)

• Blood Vessels• Digestive System• Bronchioles• Sphincters

– Glands• Adrenal• Digestive glands

Negative Feedback Control System

Controlled variable

Effector Sensor

Comparator Set point

+

-

Sensory Input

Autonomic Control Centers

Autonomic Outflow-Sympathetic and Parasympathetic Divisions dual innervation of viscera-

• Somatic efferents • • • • Sympathetic efferents • • • • Parasympathetic efferents

ACh

ACh

ACh ACh

NA

nAChR

mAChR(M1-5)

nAChR

nAChR

Alpha/beta R

CNS PNS

Cellular Organization

Cellular Organization • First Order Neurons

ACh

ACh

ACh

CNS PNS

• Cell bodies in CNS • Axons in PNS • Myelinated • Cholinergic

Cellular Organization • Second Order Neurons of ANS Divisions

ACh

NA

nAChR

nAChR

• Cell bodies in ganglia • Nicotinic ACh receptors • Axons in PNS • Unmyelinated

CNS PNS

• Sympathetic: adrenergic • Parasympathetic: cholinergic

Cellular Organization • Target Cells and Receptors

• Somatic efferents: Striated muscle • Nicotinic ACh receptors

• Autonomic efferents: • Smooth muscle • Cardiac muscle • Glands

• Receptors: • Sympathetic innervation:

Adrenergic receptors • Parasympathetic innervation:

Muscarinic ACh receptors

Sympathetic Pathways

Eye Salivary glands

Bronchial tree

Heart

Liver

GI tract

Adrenal medulla

Urinary bladder

Sex organs

Cervical Thoracic

Lumbar

Sacral

Prevertebral ganglia

Paravertebral ganglia

Sympathetic Pathways

Eye Salivary glands

Bronchial tree

Heart

Liver

GI tract

Adrenal medulla

Urinary bladder

Sex organs

Cervical Thoracic

Lumbar

Sacral

Sympathetic Pathways

Prevertebral ganglia

Paravertebral ganglia

Eye Salivary glands

Bronchial tree

Heart

Liver

GI tract

Adrenal medulla

Urinary bladder

Sex organs

Cervical Thoracic

Lumbar

Sacral

Sympathetic Pathways

Prevertebral ganglia

Paravertebral ganglia

Table below gives you an overview of the CNS origin, the paravertebral orprevertebral ganglia involved, and the targets of sympathetic efferents:

a1 a2 b1 b2 b3

↑cAMP ↑cAMP ↑cAMP↑IP3 /DAG ↓ cAMP

↑ I K+

↓ I Ca2+ ↑ PKA ↑ PKA ↑Ca2+

↑ PKC ↑ PKA

Adrenergic Receptors

ISO>A>NA NA>AResponsiveness-NA>A>ISO

* ISO - isoproterenol

RECEPTOR SUBTYPE TISSUE EFFECTS

α1 Vascular smooth muscle

Genitourinary smooth muscleIntestinal smooth muscleHeartLiver

Contraction

ContractionRelaxation↑ Inotropy and excitabilityGlycogenolysis and gluconeogenesis

α2 Pancreatic β-cellsPlateletsNerve (pre-synaptic) Vascular smooth muscle

↓ Insulin secretionAggregation↓ Norepinephrine releaseContraction

β1 HeartHeartRenal juxtaglomerular cells

↑ Chronotropy and inotropy↑ AV-node conduction velocity↑ Renin secretion

β2 Smooth muscleLiver

Skeletal muscle

RelaxationGlycogenolysis and gluconeogenesisGlycogenolysis and K+ uptake Vasculature*

β3 Adipose Lipolysis      

Physiological effects of Adrenergic Receptor activation

The overall effect of the catecholamines is to increase glucose production

Eye Salivary glands

Bronchial tree

Heart

Liver

GI tract

Adrenal medulla

Urinary bladder

Sex organs

Cervical Thoracic

Lumbar

Sacral

CN III CN VII CN IX CN X

Distinct parasympathetic ganglia

Terminal parasympathetic ganglia embedded in organ walls

Parasympathetic Pathways

Distinct Parasympathetic Ganglia

Ciliary ganglion

Pterygopalatine ganglion

Otic ganglion

Submandibular ganglion

Pic

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: co

pyr

igh

ted

ma

teria

l, w

ith p

erm

issi

on

Eye Salivary glands

Bronchial tree

Heart Liver GI tract Adrenal medulla

Urinary bladder

Sex organs

Cervical Thoracic

Lumbar

Sacral

CN III CN VII CN IX CN X

Distinct parasympathetic ganglia

Terminal parasympathetic ganglia embedded in organ walls

Parasympathetic Pathways

Eye Salivary glands

Bronchial tree

Heart

Liver

GI tract

Adrenal medulla

Urinary bladder

Sex organs

Cervical Thoracic

Lumbar

Sacral

CN III CN VII CN IX CN X

Distinct parasympathetic ganglia

Terminal parasympathetic ganglia embedded in organ walls

Parasympathetic Pathways

CNS origin, either distinct parasympathetic ganglia or terminal ganglia, and their target organs are presented in the table below:

The nerve fibers that innervate the adrenal medulla are best described as•Adrenergic sympathetic•Cholinergic sympathetic•Adrenergic parasympatheticCholinergic parasympathetic

Which of the following is caused by activity in the sympathetic system?•Decreased heart rate•Cutaneous vasoconstriction•Increased gastric secretion•Constriction of the pupil•Erection of the penis

Sweat glands are innervated by•Parasympathetic cholinergic postganglionic fibers•Sympathetic cholinergic postganglionic fibers•Sympathetic adrenergic postganglionic fibers•Parasympathetic cholinergic preganglionic fibersSympathetic cholinergic preganglionic fibers

The high ratio of postganglionic to preganglionic fibers in the sympathetic system has the physiologic result that•Convergence of stimuli occurs•Synaptic transmission is slow, leading to a delay in response•Stimulation of the sympathetic nervous system leads to widespread effects•Stimulation of the sympathetic nervous system leads to very localized, discrete effects•Sympathetic effects are very weak

You administer a muscarinic blocker to your patient. This drug is most effective at blocking•The somatic neuromuscular junction•The parasympathetic ganglia•The sympathetic ganglia•The parasympathetic neuroeffector junctionThe sympathetic neuroeffector junction

M1 M2 M3 M4 M5

Muscarinic Receptors

CNS. Autonomic Ganglia. Parietal Cell

CNS.CNS.

Smooth Muscle contraction. GI Glands Secrn

Bronchial Secrn

Sweat Vasodilation*.

Cardiac; SA & AV node.

Autonomic Ganglia.

Physiological effects of Muscarinic Receptor activation

Overview

Sympathetic

Parasympathetic

CNS origin thoraco-lumbar cranio-sacral Preganglionic fiber short

myelinated cholinergic

long myelinated cholinergic

Receptor on postganglionic

nicotinic

nicotinic

Postganglionic fiber long unmyelinated noradrenergic (*)

short unmyelinated cholinergic

Divergence high low Receptor on target adrenergic (*)

muscarinic

(*) Sympathetic innervation of sweat glands: cholinergic (!) postganglionic fibers and muscarinic (!) acetylcholine receptors

Responses of Effector Organsto Autonomic Nerve Impulses

• Autonomic Control of the Pupil

Adrenergic Impulses

Cholinergic Impulses

Responses Responses Effector Organs Rec. type

Contraction (mydriasis)

Dilator muscle of pupil

α1

Contraction (miosis)

Constrictor muscle of pupil

M

Horner’s SyndromeUnilateral miosis (small pupil), commonly associated with ptosis (drooping of the upper eyelid) and facial anhydrosis (loss of sweating).Horner's syndrome is due to underactivity of the ipsilateral sympathetic outflow, which can be caused by (1) central lesions that involve the hypothalamospinalpathway (transection of the cervical spinal cord), (2) preganglionic lesions(compression of the sympathetic chain by a lung tumor), (3) postganglionic lesions at the level of the internal carotid artery (tumor in the cavernous sinus).

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Responses of Effector Organsto Autonomic Nerve Impulses

• Autonomic Control of Accommodation

Adrenergic Impulses

Cholinergic Impulses

Responses Responses Effector Organs Rec. type

Relaxation (β2) Contraction (near vision)

Ciliary muscle

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Responses of Effector Organsto Autonomic Nerve Impulses

• Autonomic Control of Cardiac Function

Adrenergic Impulses

Cholinergic Impulses

Responses Responses Effector Organs Rec. type

Increase in heart rate

Decrease in heart rate(M2)

SA Node β1

β2

Increase in contractility

Decrease in Contractility(M2)

Atria, Ventricles β1

β2

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Responses of Effector Organsto Autonomic Nerve Impulses

• Autonomic Control of the Airways

Adrenergic Impulses

Cholinergic Impulses

Responses Responses Effector Organs Rec. type

Relaxation Contraction Tracheal and bronchial muscles

β2

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Responses of Effector Organsto Autonomic Nerve Impulses

• Autonomic Control of the Urinary Bladder

Adrenergic Impulses

Cholinergic Impulses

Responses Responses Effector Organs Rec. type

Relaxation

Contraction

Detrusor muscle β2

Contraction

Relaxation

Trigone and sphincter muscle

α1

Autonomic Control of Reproductive Organs

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Pharmacological Influence on Autonomic Function

Drug Receptor Function Medical use

Atenolol

1 adrenergic Antagonist Hypertension

Salbutamol 2 adrenergic Agonist Asthma (bronchodilator)

Atropine muscarinic Antagonist Mydriatic; Reduction of drooling in Parkinson’s disease

M1 M2 M3 M4 M5

Muscarinic Receptors

CNS. Autonomic Ganglia. Parietal Cell

CNS.CNS.

Smooth Muscle contraction. GI Glands Secrn

Bronchial Secrn

Sweat Vasodilation*.

Cardiac; SA & AV node.

Autonomic Ganglia.

Physiological effects of Muscarinic Receptor activation

A middle aged woman was carried to the district hospital in Murewa in a semiconscious state. Her husband reported that when he returned home from work he had found his 45 year old wife, Sibongile lying on the bed moaning,unable to move and barely conscious. On the bed there was vomitus and a wet patch. He said that when he had left in the morning she had been well but he had noticed that since the day before she seemed to have been upset aboutsomething and had barely talked to him; but he couldn’t think of a reason why. Asked if his wife took any medications, he said no. But then his neighbour who had accompanied him said that he had noticed there was a “Ketokil” tin in the bedroom and there was an empty cup near it. He explained that Ketokil was the stuff they used to kill weeds.On examination, the physician noted that the patient had labored respiration (8 breaths per minute) and that she seemed to be drooling. Her pulse rate was 45 bpm. Auscultation of the thorax revealed rhonchi and auscultation of the abdomen showed increased abdominal sounds. Meanwhile the hospital pharmacist reported that the active ingredient of Ketokil was parathion.1. What symptoms do you expect following intoxication with organophosphates?

2. How do you explain these symptoms from a biochemical-physiological view point?

3. What kind of therapeutic intervention do you suggest? Justify your ideas.

•Parasympathetic Vasodilation: •Endothelium Derived Relaxing Factor; NO(nitric oxide)

ACh activates Muscarinic (M3) rec. to initiate NO production via eNOS. NO freely diffusable and produces smooth muscle relaxation / vasodilation.

Muscarinic Receptor Agonists

Which clinical conditions would they benefit?

Eye:

Muscarinic agonists

Contract circular muscle

Miosis Outflow of aqueous humor

↓ intraocular pressureBenefits glaucoma

GIT Bladder, urinary tract

Contract smooth muscle

↑ Motility

Restore GIT and UT motility after anesthesia/surgery

Salivary glands

↑ Salivation Benefits xerostomia

Muscarinic Receptor Agonists - Parasympathomimetics

Methacholine Carbachol Bethanechol Pilocarpine

Derivatives of ACh

Acetylcholine is NOT used clinically – very short t1/2

Differ in pharmacokinetic properties, resistance to ChEsterase and their affinity to both Nm and Muscarinic rec.

Methacholine: used in diagnosis of asthma

Carbachol: affinity for Nm rec resistant to ChE used topically – as a miotic agent to treat glaucoma

Asthmatics are more sensitive to the bronchial secreting actions of methacholine

Bethanechol: Selective for Muscarinic receptors

Uses: to ↑ GIT and urinary tract motility

Pilocarpine:Uses topically as a miotic in glaucoma

as a sialogogue to ↑ saliva secretion

Muscarinic Receptor Antagonists “Parasympatholytics”

Mode of Action

Bind to muscarinic receptors and prevent Ach from exerting its effects Competitive antagonists

Prototype: ATROPINE (Plant alkaloid from Atropa belladonna)

Actions: Pupil dilation Tachycardia ↓ secretions (salivary, bronchial, GIT)

Clinical Uses of Atropine:

1. To produce mydriasis for ophthalmological examination (applied topically) 2. To reverse sinus bradycardia caused by excessive vagal tone 3. To inhibit excessive salivation and mucus secretion during anesthesia and surgery 4. To counteract the effects of muscarine poisoning AND poisoning with anticholinesterases

RECEPTOR SUBTYPE TISSUE EFFECTS

α1 Vascular smooth muscle

Genitourinary smooth muscleIntestinal smooth muscleHeartLiver

Contraction

ContractionRelaxation↑ Inotropy and excitabilityGlycogenolysis and gluconeogenesis

α2 Pancreatic β-cellsPlateletsNerve (pre-synaptic) Vascular smooth muscle

↓ Insulin secretionAggregation↓ Norepinephrine releaseContraction

β1 HeartHeartRenal juxtaglomerular cells

↑ Chronotropy and inotropy↑ AV-node conduction velocity↑ Renin secretion

β2 Smooth muscleLiver

Skeletal muscle

RelaxationGlycogenolysis and gluconeogenesisGlycogenolysis and K+ uptake Vasculature*

β3 Adipose Lipolysis      

Physiological effects of Adrenergic Receptor activation

Epinephrine & Norepinephrine Affinities for a and b adrenoceptors

Epinephrine;-higher affinity for b adrenoceptors has a predominant ‘b’ effect. At higher concentrations it has an effect on a1 adrenoceptors. At high doses effective at treating anaphylaxis and used for vasoconstriction in cojunction with local anaesthetic.

Norepinephrine: Has affinity for a1 and b1 adrenoceptors. Little affinity for b2 adrenoceptors.

1a Adrenergic receptor agonists & antagonists: Clinical Uses

Major physiological response following a1 receptor activation is increased peripheral resistance & genitourinary smooth muscle contraction.

a1 Agonists Methoxamine: Limited use except for hypotension from circulatory shock. Side effects: Reflex vagal sinus bradycardia Phenylephrine: Used as nasal decongestant. Side efffects: Hypertension

a1 Antagonists

Prazosin: Used for treatment of hypertension and Benign Prostatic Hypertrophy Side effects: Postural orthostatic/ hypotension related to 1st dose phenomena. Tamsulosin: Used for Benign Prostatic Hypertension. More selective for genitourinary smooth muscle receptor subtype (a1A). Less postural / orthostatic hypotension

Major physiological response following a2 rec. activation is reduced NE release

2a Adrenergic receptor agonists & antagonists: Clinical Uses

a2 Agonists

Clonidine: Used for treatment of hypertension (decreased peripheral sympathetic outflow) and opioid withdrawal. Side Effects: Bradycardia & hypotension.

a2 Antagonists

Yohimbine: Previously used for male impotence. Side Effects: bradycardia and hypertension

Stimulation of β1-adrenergic receptors causes an increase in heart rate and the force of contraction, resulting in increased cardiac output. Stimulation of β2-adrenergic receptors causes relaxation of vascular, bronchial, and gastrointestinal smooth muscle.

Non Selective b Adrenergic Receptor Agonists: Clinical Uses

Non selective b receptor agonists: Isoproterenol: Emergency arrhythmias & bronchospasm. More selective agonists now available. Side effects: Hypertension, palpitations, tremor

Selective b1 receptor agonists: Dobutamine: Has prominent inotropic effects resulting in increased contractility and cardiac output. Short half life due to COMT metabolism. Used in the ACUTE management of heart failure.

Selective b2 receptor agonists

Albuterol: Used as ‘asthma reliever’. Rapid action (15 min) relative short duration (4-6 hours). Salmeterol: Long-acting beta agonists (LABA’s). Have lipophilic side chains that resist degradation. Enhance duration (12-24-hours), used for prevention of bronchoconstriction.

Used for treatment of Asthma. Pulmonary drug delivery enhances selectivity of β2-adrenoceptors agonists, avoids cardiac (b1) and skeletal (b2) side effects.

β-Adrenergic Antagonists: Clinical Uses

Propranolol: Clinically used for Hypertension, angina. Side effects include sedation (central effect) and dyspnoea. Timolol: As an ocular formulation used in the treatment of glaucoma. MOA unknown but thought to be through reduced production of aqueous humor.

Most significant effect these compounds have to reduce the chronotropic and inotropic actions of endogenous catecholamines at cardiac β1-receptors, resulting in decreased heart rate and myocardial contractility. Blockade of b1 receptors in kidney to reduce renin secretion also clinically relevant in reducing fluid overload and vasomotor tone. Are first line drugs used in treatment of hypertension. Blockade of b2 receptors is clinically undesirable.

Non-selctive b adrenoceptor antagonists

β1-Selective Adrenergic Antagonists: Clinical Uses

Esmolol Clinically used in emergency b receptor blockade as in a thyroid storm (Half-life ~ 4 minutes). Atenolol: Clinically used in treatment of hypertension and angina, improves life expectancy in patients with HF#.

Side Effects: Similar to Propanolol but much less severe.

Partial b1 Agonists: Clinical Uses*

As a partial agonist they are effective at reducing the effect of endogenous NE at b1 receptors. This leads to smaller decreases in resting heart rate & blood pressure (compared to b1 receptor antagonists). Acebutolol Clinically used for treatment of hypertension in patients with bradycardia or low cardiac reserve.

* Partial agonists are effectively weak ‘antagonists’

# Clinical benefit in HF through volume reduction (↓afterload) via ↓ renin production. Contraindicated in severe HF

Catecholamine Metabolism: MAO & COMT

Mono Amine Oxidase (MAO): Mitochondrial enzyme. Isoforms; MAO A & MAO B MAO A: Serotonin > NE > Dopamine & tyramine MAO B: Dopamine > serotonin>NE Catechol-O-methyl transferase (COMT): Cytosolic enzyme expressed primarily in liver

Inhibitors of Re-Uptake: Cocaine: Inhibits NET. Tricyclic Antidepressants (TCA’s) inhibit NET. Imipramine: Used for treating mild depression. Side effects Postural hypotension & tachycardia Inhibitors of Storage: Reserpine blocks VMAT Tyramine transported via VMAT & displaces

vesicular NE.

Inhibitors of Metabolism: MAO Inhibitors used for treatment of mild depression. Phenelzine: Non selective MAO Inhibitor. Implicated in elevated tyramine leading to hypertensive crisis Selegiline: Selective MAO B Inhibitor. Safer with respect to dietary restriction also useful for Parkinson’s

Drugs Affecting Storage Reuptake & Storage

Inhibitors of Re-uptake and Storage Amphetamines (i) Displaces endogenous

catecholamines from storage vesicles

(ii) blocks NET (iii) a weak inhibitor of MAO Methylphenidate: Used for ADHD Pseudoephidrine: Used for nasal

decongestion